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Cited by 41Diabetes and associated disordersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

Slc11a1 Enhances the Autoimmune Diabetogenic T-Cell Response by Altering Processing and Presentation of Pancreatic Islet Antigens

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Dai, Yang D., Marrero, Idania G., Gros, Philippe, Zaghouani, Habib, Wicker, Linda S., Sercarz, Eli E.·2009·Diabetes
DOI 10.2337/db07-1608PMC PMC2606865
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Abstract

OBJECTIVE: Efforts to map non-major histocompatibility complex (MHC) genes causing type 1 diabetes in NOD mice identified Slc11a1, formerly Nramp1, as the leading candidate gene in the Idd5.2 region. Slc11a1 is a membrane transporter of bivalent cations that is expressed in late endosomes and lysosomes of macrophages and dendritic cells (DCs). Because DCs are antigen-presenting cells (APCs) known to be critically involved in the immunopathogenic events leading to type 1 diabetes, we hypothesized that Slc11a1 alters the processing or presentation of islet-derived antigens to T-cells. RESEARCH DESIGN AND METHODS: NOD mice having wild-type (WT) or mutant Slc11a1 molecules and 129 mice having WT or null Slc11a1 alleles were examined for parameters associated with antigen presentation. RESULTS: We found that Slc11a1 enhanced the presentation of a diabetes-related T-cell determinant of GAD65, and its function contributed to the activation of a pathogenic T-cell clone, BDC2.5. An enhanced generation of interferon (IFN)-gamma-producing T-cells was also associated with functional Slc11a1. The alteration of immune responsiveness by Slc11a1 genotype did not correlate with altered MHC class II expression in DCs; however, functional Slc11a1 was associated with accelerated phagocytosis and phagosomal acidification in DCs. CONCLUSIONS: The association of variants encoding Slc11a1 with type 1 diabetes may reflect its function in processing and presentation of islet self-antigens in DCs. Thus, non-MHC genes could affect the MHC-restricted T-cell response through altered antigen processing and presentation.

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  • Many effectors of microbial iron withdrawal have direct or indirect impact on acquired immunity, such as the function of lymphocyte subsets.

    “Furthermore, many effectors of microbial iron withdrawal have direct or indirect impact on acquired immunity such as the function of lymphocyte subsets (Dai et al., 2009;Hedges et al., 2013;Lee et al., 2020;Stober et al., 2007).”

    From Iron in infection and immunity (2020) · cites this paper as Dai et al., 2009

    The Discussion ('Proinflammatory activity of Slc11a1') reports that Slc11a1 promotes a Th1 T-cell response, supporting an effect on acquired immunity. The Discussion ('Enhanced intracellular vesicle fusion and/or acidification by Slc11a1') describes possible deprivation of divalent cations during intracellular infection, but does not establish iron withdrawal specifically. No page numbers are available in our copy. (LLM, conf=0.82)

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Authors
Dai, Y. D., Marrero, I. G., Gros, P., Zaghouani, H., Wicker, L. S., & Sercarz, E. E.
Affiliations
  • Torrey Pines Institute For Molecular Studies (US)
  • McGill University (CA)
  • University of Missouri (US)
  • University of Cambridge (GB)
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2009-01-01
Volume
58
Issue
1
Pages
156-164
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db07-1608
PMC
PMC2606865
OpenAlex
W2163081237
Cited by
41
References
47
Citations by year
2024: 1 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2014: 5 · 2013: 5 · 2012: 3
FWCI
3.00
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Wellcome Trust (061859/B/00/Z)
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
SLC11A1, NRAMP1, type 1 diabetes, autoimmune diabetes, dendritic cells, antigen processing and presentation, GAD65, interferon-gamma, phagosome acidification, phagocytosis, non-MHC genes, NOD mice, MHC class II
MeSH terms
Natural Resistance-associated Macrophage Protein 1, Animals, Histocompatibility Antigens Class II, Cells, Cultured, Dendritic Cells, Diabetes Mellitus, Type 1, Flow Cytometry, Islets of Langerhans, Macrophages, Phagocytosis, T-Lymphocytes, Blotting, Western, Autoimmunity, Mice, Inbred NOD, Antigen Presentation, B7-1 Antigen, Mice, Knockout, Cation Transport Proteins, Cell Proliferation, Mice

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